Throughout this application various publications are referenced, many in parenthesis. Full citations for each of these publications are provided at the end of the Detailed Description and throughout the Detailed Description. The disclosures of each of these publications in their entireties are hereby incorporated by reference in this application.
Biological therapy (sometimes called immunotherapy, biotherapy, or biological response modifier therapy) is a relatively new addition to the family of cancer treatments that also includes surgery, chemotherapy, and radiation therapy. Biological therapies use the body's immune system, either directly or indirectly, to fight cancer or to lessen the side effects that may be caused by some cancer treatments.
The immune system is a complex network of cells and organs that work together to defend the body against attacks by “foreign,” or “non-self,” invaders. This network is one of the body's main defenses against disease. It works against disease, including cancer, in a variety of ways. For example, the immune system may recognize the difference between healthy cells and cancer cells in the body and work to eliminate those that become cancerous. Cancer may develop when the immune system breaks down or is not functioning adequately. Biological therapies are designed to repair, stimulate, or enhance the immune system's responses.
Immune system cells include lymphocytes and monocytes. Lymphocytes are a type of white blood cell found in the blood and many other parts of the body. Types of lymphocytes include B cells, T cells, and Natural Killer cells. B cells (B lymphocytes) mature into plasma cells that secrete antibodies (immunoglobulins), the proteins that recognize and attach to foreign substances known as antigens. Each type of B cell makes one specific antibody, which recognizes one specific antigen. T cells (T lymphocytes) directly attack infected, foreign, or cancerous cells. T cells also regulate the immune response by signaling other immune system defenders. T cells work primarily by producing proteins called lymphokines. Natural Killer cells (NK cells) produce powerful chemical substances that bind to and kill any foreign invader. They attack without first having to recognize a specific antigen. Monocytes are white blood cells that can swallow and digest microscopic organisms and particles in a process known as phagocytosis. Monocytes can also travel into tissue and become macrophages.
Cells in the immune system secrete two types of proteins: antibodies and cytokines. Antibodies respond to antigens by latching on to, or binding with, the antigens. Specific antibodies match specific antigens. Cytokines are substances produced by some immune system cells to communicate with other cells. Types of cytokines include lymphokines, interferons, interleukins, and colony-stimulating factors. Cytotoxic cytokines are released by a type of T-cell called a cytotoxic T-cell (CTL). These cytokines attack cancer cells directly.
Cancer vaccines are a form of biological therapy currently under study. Vaccines for infectious diseases, such as measles, mumps, and tetanus, are effective because they expose the body's immune cells to weakened forms of antigens that are present on the surface of the infectious agent. This exposure causes the immune cells to produce more plasma cells, which make antibodies. T-cells that recognize the infectious agent also multiply. These activated T-cells later remember the exposure. The next time the agent enters the body, cells in the immune system are already prepared to respond and stop the infection.
For cancer treatment, researchers are developing vaccines that may encourage the patient's immune system to recognize cancer cells. These vaccines may help the body reject tumors and prevent cancer from recurring. Cancer vaccines given when the tumor is small may be able to eradicate the cancer. Early cancer vaccine clinical trials involved mainly patients with melanoma. Currently, cancer vaccines are also being studied in the treatment of many other types of cancer, including lymphomas and cancers of the kidney, breast, ovary, prostate, colon, and rectum.
Multiple myeloma (MM) is one form of cancer. Allogeneic stem cell transplantation has been applied to patients with multiple myeloma (MM) to induce disease remission, but many patients still experience disease relapse and die of the disease. There is a strong correlation between graft-versus-host disease (GVHD) and graft-versus-myeloma (GVM) in MM patients, so those patients who develop GVHD have a lower risk of disease relapse (Desikan et al. 2000). This observation suggests that the GVM effect of stem cell transplantation may be part of the more global GVH reactions due to minor histocompatibility differences between the donor and the recipient. Therefore, GVM is achieved at the expense of GVHD. As a result, although these patients have a lower risk of disease relapse, such advantage may not be translated into improved survival because a high proportion of these patients die due to complications associated with GVHD. If a myeloma antigen can be specifically targeted, tumor-specific donor CTL could be generated and administered to these patients following T cell-depleted allogeneic stem cell transplantation to enhance the GVM effect without inducing GVHD. The myeloma idiotypic protein is clone specific and has been previously used in the autologous settings (Lim and Bailey-Wood 1999; Wen et al. 1998; Reichardt et al. 1999; Massaia et al. 1999; Osterborg et al. 1999). However, the clinical results in the autologous settings have been disappointing due probably to the weak immunogenicity of the idiotypes and low effector:target ratio generated by the vaccines.
Therefore, there is a need for studies into other novel tumor antigens in MM that elicit consistent and strong tumor-specific immune responses that produce effective antitumor effects.
In addition to the idiotypes, T lymphocyte targets on myeloma cells that may be suitable molecules for enhancement of GVM without inducing GVHD include MUC-1 (Noto et al. 1997), mutant ras oncogene protein (Corradini et al. 1993) and the new class of tumor antigens, known as CT (cancer-testis) antigens (Olds and Chen 1998). The CT antigens include members of the MAGE family, BAGE, GAGE and NY-ESO-1. They are normal testicular antigens expressed aberrantly in tumor cells. Their restricted normal tissue expression makes them ideal molecules for immune targeting. CT antigens are expressed in some myeloma cells (Lim et al. 1999; Van Varen et al. 1999). Anti-MAGE-A3 CTL clones raised from normal healthy donors could lyse myeloma cells in an HLA-A1- and HLA-A2-specific manner (Van Baren et al. 1999).
Sp17 is a protein of apparent molecular mass of 24.5 kDa that is involved in acrosome reactions in spermatozoa. It has, in the last few years, been the target of investigation as an immunocontraceptive. It is a highly immunogenic protein in vivo, and previous studies have shown a high incidence for the spontaneous development of autoantibodies against Sp17 in vasectomized normal healthy males (Lea et al. 1997). Both B and T cell epitopes of Sp17 have also been defined in mice (Lea et al. 1998).